The purpose of the research outlined in this proposal is to elucidate further the precise specificity of the receptor for antigen on thymus-derived (T) lymphocytes. Experiments will continue on the characterization of the DNA synthetic response of guinea-pig T cells to chemically defined antigenic determinants. This definition of the specificity of response will be paralleled by attempts to study the specificity of antigen binding, by cells and by isolated receptor molecules. A search for inhibitors of two types will be made: 1) those that compete with antigen for binding to the receptor, (i.e., non-stimulatory ligands); and 2) specific anti-receptor antibodies (anti-idiotypic antibodies). Using these alternate ligands as immunoadsorbents, the next step will be to isolate such receptors in soluble form. Binding of antigen by intact T cells, measured either as activation or as binding, and binding by isolated receptors will then be compared using model compounds known to be chemically similar, but differing in their ability to activate T cells. By this means one can compare binding of antigen with cell activation. If these two functions are congruent, then one can be quite certain that cell activation results from specific binding of unmodified antigen. If they are not congruent, then antigen binding by receptor is not sufficient to activate a T cell. This leads to interestng possibilities for further studies of T cell activation by antigen, probably involving cell surface interactive phenomena, and perhaps cell-cell cooperation. The isolated receptor will also be characterized by immunochemical and biochemical means, its affinity constants determined, its degree of cross-reactivity and specificity, its stereospecificity, its molecular size and structure, as well as its antigen binding, both to free antigen and to cell-surface bound antigen. From these studies, the T cell receptor will be compared with B cell receptors specific for the same antigenic determinant, to see if the immune system has generated a unique or more than one system of antigen recognition.